an efficacy and safety study of palovarotene for the treatment of fibrodysplasia ossificans progressiva.

Conditions: Fibrodysplasia Ossificans Progressiva

Summary: fibrodysplasia ossificans progressiva (fop) is a rare, severely disabling disease characterized by heterotopic ossification (ho) often associated with painful, recurrent episodes of soft tissue swelling (flare-ups) that lead to ankyloses of major joints with cumulative and irreversible loss of movement and disability.

one of the primary objectives was to evaluate the efficacy of palovarotene in decreasing new ho in participants with fop as assessed by low-dose, whole body computed tomography (wbct), excluding head, compared to untreated participants from clementia's fop natural history study (study pvo-1a-001, nhs). the other primary objective was to evaluate the safety of palovarotene in participants with fop. this study was conducted in three parts. part a was the main part of the study, part b, the 2-year (24-month) extension and part c was an up-to-2-year post last dose of study treatment follow-up for skeletally immature participants. participants in part a and b received a chronic/flare-up dosing regimen of palovarotene for up to 4 years (48 months) as follows: * chronic treatment: orally administered 5 mg palovarotene once daily. * flare-up treatment: orally administered 20 mg palovarotene once daily for 4 weeks (28 days) followed by orally administered 10 mg palovarotene once daily for 8 weeks (56 days). flare-up treatment may be extended until the investigator determines that the flare-up has resolved. note that all dosing was weight-adjusted in skeletally immature participants (those under the age of 18 years with less than 90% skeletal maturity on hand/wrist x-rays performed at screening). in part c, participants who were enrolled in parts a or b who discontinued the study and were skeletally immature were invited back to participate in the off-treatment safety follow-up. no new participants were enrolled into part c.

Eligibility criteria:
key inclusion criteria: * written, signed, and dated informed subject/parent consent; and for subjects who are minors, age-appropriate assent (performed according to local regulations). * males or females at least 4 years of age. * no flare-up symptoms within the past 4 weeks, including at the time of enrollment. * abstinent or using two highly effective forms of birth control. * accessible for treatment and follow-up; able to undergo all study procedures including low-dose wbct (excluding head) without sedation. key exclusion criteria: * weight \<10 kg. * concomitant medications that are strong inhibitors or inducers of cytochrome p450 (cyp450) 3a4 activity; or kinase inhibitors such as imatinib. * amylase or lipase \>2x above the upper limit of normal (uln) or with a history of chronic pancreatitis. * elevated aspartate aminotransferase or alanine aminotransferase \>2.5x uln. * fasting triglycerides \>400 mg/dl with or without therapy. * female subjects who are breastfeeding. * subjects with uncontrolled cardiovascular, hepatic, pulmonary, gastrointestinal, endocrine, metabolic, ophthalmologic, immunologic, psychiatric, or other significant disease. * simultaneous participation in another clinical research study (other than palovarotene studies) within 4 weeks prior to screening; or within five half-lives of the investigational agent, whichever is longer. * any reason that, in the opinion of the investigator, would lead to the inability of the subject and/or family to comply with the protocol.

Keywords: interventional study clinical trial phase 3 efficacy and safety heterotopic ossification flare-up palovarotene retinoic acid receptor agonist retinoic acid receptor gamma agonist clementia myositis ossificans progressiva munchmeyer's disease fop fop variants